Effects of simvastatin on neuroprotection and modulation of Bcl-2 and BAX in the rat quinolinic acid model of Huntington's disease.
A possible neuroprotective role has been recently suggested for 3H3MGCoA reductase inhibitors. Here, we sought to determine whether simvastatin exerts a neuroprotective effect in our rat model of HD. Rats were surgically administered quinolinic acid and treated with simvastatin 1mg/kg intraperitoneally (i.p.) once daily up to 2 or 8 weeks. Two more groups of animals received a pretreatment with 1mg/kg simvastatin i.p. for 2 weeks before the QA lesion and then were treated with simvastatin for the following 2 weeks or 8 weeks, respectively. In the simvastatin treated groups (both pretreated and non-pretreated), striatal lesion size was about 36% smaller while neuronal counts where higher than in the vehicle treated ones at 2 weeks. The neuroprotective effects of simvastatin was still evident at 8 weeks post lesion, where the non-pretreated group had a 8% smaller lesion size than the saline group, and the pretreated group had an 11% smaller lesion size than the saline group. Simvastatin also induced immunoreactivity for Bcl-2, an anti-apoptotic factor, on one hand, and down-regulated immunoreactivity for Bax, a proapoptotic factor. Bcl-2/Bax modulation can account, at least partly, for the beneficial effect of simvastatin in our rodent model of striatal degeneration. Our findings show that statins could be explored as possible neuroprotective agents for neurodegenerative disorders such as HD.
Patassini
Stefano
S
Laboratory of Neuroanatomy, Santa Lucia Foundation IRCCS, European Center for Brain Research, Rome, Italy.
Giampà
Carmela
C
Martorana
Alessandro
A
Bernardi
Giorgio
G
Fusco
Francesca R
FR
D000818:Animals; D002135:Calcium-Binding Proteins / Q000378:metabolism; D004609:Eliminative Behavior, Animal; D006816:Huntington Disease / Q000139:chemically induced / Q000188:drug therapy / Q000378:metabolism; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors / Q000627:therapeutic use*; D008297:Male; D010320:Parvalbumins / Q000378:metabolism; D010751:Phosphopyruvate Hydratase / Q000378:metabolism; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000378:metabolism*; D017378:Quinolinic Acid; D051381:Rats; D017208:Rats, Wistar; D019821:Simvastatin / Q000627:therapeutic use*; D013997:Time Factors; D051028:bcl-2-Associated X Protein / Q000378:metabolism*
C494828:Bax protein, rat; D002135:Calcium-Binding Proteins; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors; D010320:Parvalbumins; D019253:Proto-Oncogene Proteins c-bcl-2; D051028:bcl-2-Associated X Protein; D019821:Simvastatin; D010751:Phosphopyruvate Hydratase; D017378:Quinolinic Acid